The invention relates to compounds useful as xcex23-adrenoreceptor agonists.
For many individuals, a tendency to experience weight problems and even obesity is often symptomatic of disease or disorders of the metabolism associated with serious and even life-threatening conditions. The decade of the 1990""s witnessed dramatic increases in diabetes and obesity in the United States, and at the same time, Americans showed little improvement in eating habits or increasing their physical activity. In a study published in the Journal of the American Medical Association, the Center for Disease Control and Prevention (CDC) found a 61 percent increase in the percentage of Americans who are obese from 1991 to 2000 (12.0 percent to 19.8 percent), and a 49 percent increase in the percentage of Americans who have diabetes from 1990 to 2000 (4.9 percent to 7.3 percent). About nine percent of the national health care expenditures in the United States are directly related to obesity and physical inactivity. In 1997, the health care costs associated with diabetes were $98 billion.
A wide variety of approaches to the alleviation of obesity have ebbed and flowed though modem culture, ranging from a diverse collection of dietary strategies, to drugs, to surgical interventions, to hypnosis. All have met with indifferent success at best. A great deal of the difficulty in the art and practice of obesity and weight management has been a consequence of attention focused on the control of appetite, and reducing the amount of food intake. It has long been the belief of many that only by the control of caloric intake is it possible to regulate body weight and fat deposition and utilization. Since appetite is controlled and regulated in the brain, brain pharmacology and the alteration of brain chemistry has been a primary focus of weight regulation and control efforts. Only in very recent times has obesity been addressed in relation to the metabolic pathways of the body and their role and import in fat storage and usage in the body.
Recent research has elucidated some of the mechanisms of obesity and weight gain, and has revealed that much of the limitation of prior and current weight-loss techniques stems from the fact that they are biochemically, and particularly metabolically, unsound and incapable of stimulating, regulating and modulating metabolism of fats in adipose tissues. Increasing efforts have been directed to biochemical research into the mechanisms of fat deposition and metabolism.
Among the biochemical work of note has been the recent recognition of a role of xcex2-adrenoreceptor activity in the metabolism of fats. It has been recognized that agonists for xcex2-adrenoreceptors have, in some cases, produced marked weight loss in animals, particularly humans and other mammals. More recently, the loss of weight has been identified with the xcex2-adrenoreceptor sub-type, xcex23-adrenoreceptor. It has been demonstrated that compounds that are significant xcex23-adrenoreceptor agonists produce marked weight loss in animals, particularly humans and other mammals, and that the loss is sustained with continuation of the administration of such compounds. These compounds provide potent regulation of fat metabolism. The compounds employed to date are also agonists for the xcex21-adrenoreceptor and the xcex22-adrenoreceptor sites. The lack of selectivity represents unwanted side effects of such compounds, and the compounds known as xcex23-adrenoreceptor agonists to-date are not suitable candidates for therapeutic usage because of undesirable side effects.
There is a need in the art for therapeutic agents that are highly potent and highly selective xcex23-adrenoreceptor agonists for effective stimulation, regulation and modulation of metabolism of fats in adipose tissues.
The present invention provides tetraisoquinoline compounds useful as xcex23-adrenoreceptor agonists. In a preferred embodiment, the compounds of the invention are highly specific xcex23-adrenoreceptor agonists that exhibit little or no affinity for the other xcex2-adrenoreceptors.
In one aspect, the present invention provides compounds of the formula: 
wherein:
each R1 is xe2x80x94NHS(O)mR, wherein R is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle;
each X is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxy, nitro, amino, and substituted amino;
R2 is benzyl or benzyl substituted with one or more substituents selected from the group consisting of halo, CF3, hydroxy, nitro, alkoxy, substituted alkoxy, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, and substituted amino of formula xe2x80x94NHRxe2x80x2 or xe2x80x94Rxe2x80x2Rxe2x80x2, wherein each Rxe2x80x2 is alkyl, substituted alkyl, xe2x80x94C(O)Y, xe2x80x94C(O)NHY, or xe2x80x94C(O)SY, wherein Y is alkyl or substituted alkyl;
R3 is H or alkyl;
n is 0-3;
m is 1-2;
p is 1-4;
the sum of n and p is 1-4;
and pharmaceutically acceptable salts thereof.
In another aspect, the invention provides pharmaceutical compositions comprising at least one compound of Formula I and at least one pharmaceutically acceptable carrier. In a further aspect, the invention provides a method of treating obesity and related conditions that would benefit from stimulating, regulating and modulating metabolism of fats in adipose tissues, specifically by interaction with the xcex23-adrenoreceptor. The method involves administering a compound of Formula I, optionally with one or more pharmaceutically acceptable carriers, to an animal, preferably a human or other mammal.
The present invention now will be described more fully hereinafter. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
The following terms as used herein have the meanings indicated.
As used in the specification, and in the appended claims, the singular forms xe2x80x9caxe2x80x9d, xe2x80x9canxe2x80x9d, xe2x80x9cthexe2x80x9d, include plural referents unless the context clearly dictates otherwise.
The term xe2x80x9calkylxe2x80x9d refers to hydrocarbon chains typically ranging from about 1 to about 12 carbon atoms in length, preferably 1 to about 6 atoms, and includes straight and branched chains. The hydrocarbon chains may be saturated or unsaturated.
xe2x80x9cCycloalkylxe2x80x9d refers to a saturated or unsaturated cyclic hydrocarbon chain, including bridged, fused, or spiro cyclic compounds, preferably comprising 3 to about 12 carbon atoms, more preferably 3 to about 8.
The term xe2x80x9csubstituted alkylxe2x80x9d or xe2x80x9csubstituted cycloalkylxe2x80x9d refers to an alkyl or cycloalkyl group substituted with one or more non-interfering substituents, such as, but not limited to, C3-C8 cycloalkyl, e.g., cyclopropyl, cyclobutyl, and the like; acetylene; cyano; alkoxy, e.g., methoxy, ethoxy, and the like; lower alkanoyloxy, e.g., acetoxy; hydroxy; carboxyl; amino; lower alkylamino, e.g., methylamino; ketone; halo, e.g. chloro or bromo; phenyl; substituted phenyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d refers to an xe2x80x94Oxe2x80x94R group, wherein R is alkyl or substituted alkyl, preferably C1-C6 alkyl (e.g., methoxy or ethoxy).
xe2x80x9cArylxe2x80x9d means one or more aromatic rings, each of 5 or 6 core carbon atoms. Multiple aryl rings may be fused, as in naphthyl or unfused, as in biphenyl. Aryl rings may also be fused or unfused with one or more cyclic hydrocarbon, heteroaryl, or heterocyclic rings.
xe2x80x9cSubstituted arylxe2x80x9d is aryl having one or more non-interfering groups as substituents. For substitutions on a phenyl ring, the substituents may be in any orientation (i.e., ortho, meta or para).
xe2x80x9cHeteroarylxe2x80x9d is an aryl group containing from one to four heteroatoms, preferably N, O, or S, or a combination thereof, which heteroaryl group is optionally substituted at carbon or nitrogen atom(s) with C1-6 alkyl, xe2x80x94CF3, phenyl, benzyl, or thienyl, or a carbon atom in the heteroaryl group together with an oxygen atom form a carbonyl group, or which heteroaryl group is optionally fused with a phenyl ring. Heteroaryl rings may also be fused with one or more cyclic hydrocarbon, heterocyclic, aryl, or heteroaryl rings. Heteroaryl includes, but is not limited to, 5-membered heteroaryls having one hetero atom (e.g., thiophenes, pyrroles, furans); 5-membered heteroaryls having two heteroatoms in 1,2 or 1,3 positions (e.g., oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heteroaryls having three heteroatoms (e.g., triazoles, thiadiazoles); 5-membered heteroaryls having 3 heteroatoms; 6-membered heteroaryls with one heteroatom (e.g., pyridine, quinoline, isoquinoline, phenanthrine, 5,6-cycloheptenopyridine); 6-membered heteroaryls with two heteroatoms (e.g., pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6-membered heteroaryls with three heteroatoms (e.g., 1,3,5-triazine); and 6-membered heteroaryls with four heteroatoms.
xe2x80x9cSubstituted heteroarylxe2x80x9d is heteroaryl having one or more non-interfering groups as substituents.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d means one or more rings of 5-12 atoms, preferably 5-7 atoms, with or without unsaturation or aromatic character and at least one ring atom which is not carbon. Preferred heteroatoms include sulfur, oxygen, and nitrogen. Multiple rings may be fused, as in quinoline or benzofuran.
xe2x80x9cSubstituted heterocyclexe2x80x9d is heterocycle having one or more side chains formed from non-interfering substituents.
xe2x80x9cNon-interfering substituents are those groups that, when present in a molecule, are typically non-reactive with other functional groups contained within the molecule.
Suitable non-interfering substituents or radicals include, but are not limited to, halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkenyl, C1-C10 alkoxy, C7-C12 aralkyl, C7-C12 alkaryl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, phenyl, substituted phenyl, toluoyl, xylenyl, biphenyl, C2-C12 alkoxyalkyl, C7-C12 alkoxyaryl, C7-C12 aryloxyalkyl, C6-C12 oxyaryl, C1-C6 alkylsulfonyl, C1-C10 alkylsulfonyl, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(C1-C10 alkyl) wherein m is from 1 to 8, aryl, substituted aryl, substituted alkoxy, fluoroalkyl, heterocyclic radical, substituted heterocyclic radical, nitroalkyl, xe2x80x94NO2, xe2x80x94CN, xe2x80x94NRC(O)xe2x80x94(C1-C10 alkyl), xe2x80x94C(O)xe2x80x94(C1-C10 alkyl), C2-C10 thioalkyl, xe2x80x94C(O)Oxe2x80x94(C1-C10 alkyl), xe2x80x94OH, xe2x80x94SO2, xe2x95x90S, xe2x80x94COOH, xe2x80x94NR, carbonyl, xe2x80x94C(O)xe2x80x94(C1-C10 alkyl)xe2x80x94CF3, xe2x80x94C(O)xe2x80x94CF3, xe2x80x94C(O)NR2, xe2x80x94(C1-C10 alkyl)xe2x80x94Sxe2x80x94(C6-C12 aryl), xe2x80x94C(O)xe2x80x94(C6-C12 aryl), xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)mxe2x80x94Oxe2x80x94(C1-C10 alkyl) wherein each m is from 1 to 8, xe2x80x94C(O)NR, xe2x80x94C(S)NR, xe2x80x94SO2NR, xe2x80x94NRC(O)NR, xe2x80x94NRC(S)NR, salts thereof, and the like. Each R as used herein is H, alkyl or substituted alkyl, aryl or substituted aryl, aralkyl, or alkaryl.
xe2x80x9cHeteroatomxe2x80x9d means any non-carbon atom in a hydrocarbon analog compound. Examples include oxygen, sulfur, nitrogen, phosphorus, arsenic, silicon, selenium, tellurium, tin, and boron.
The present invention provides tetraisoquinoline compounds useful as xcex23-adrenoreceptor agonists, preferably highly selective xcex23-adrenoreceptor agonists, having the formula: 
wherein:
each R1 is xe2x80x94NHS(O)mR, wherein R is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle;
each X is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxy, nitro, amino, and substituted amino;
R2 is benzyl or benzyl substituted with one or more substituents selected from the group consisting of halo, CF3, hydroxy, nitro, alkoxy, substituted alkoxy, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, and substituted amino of formula xe2x80x94NHRxe2x80x2 or xe2x80x94NRxe2x80x2Rxe2x80x2, wherein each Rxe2x80x2 is alkyl, substituted alkyl, xe2x80x94C(O)Y, xe2x80x94C(O)NHY, or xe2x80x94C(O)SY, wherein Y is alkyl or substituted alkyl;
R3 is H or alkyl (e.g., C1-C6 alkyl such as methyl, ethyl and the like);
n is 0-3, preferably 1;
m is 1-2, preferably 2;
p is 1-4, preferably 1;
the sum of n and p is 1-4, preferably 2;
and pharmaceutically acceptable salts thereof.
As used herein, xe2x80x9csubstituted aminoxe2x80x9d encompasses mono- and disubstituted amino groups. Preferred substituents of the xe2x80x9csubstitutedxe2x80x9d groups referred to above include, but are not limited to, C1-C6alkyl, C1-C6 alkoxy, hydroxy, halo, nitro, amino, amino substituted with one or two C1-C6alkyl, CF3, xe2x80x94Oxe2x80x94CF3, phenyl (optionally substituted with one or more C1-C6alkyl, C1-C6 alkoxy, hydroxy, halo, nitro, CF3, xe2x80x94Oxe2x80x94CF3, amino, or amino substituted with one or two C1-C6alkyl), and benzyl (optionally substituted with one or more C1-C6alkyl, C1-C6 alkoxy, hydroxy, halo, nitro, CF3, xe2x80x94Oxe2x80x94CF3, amino, or amino substituted with one or two C1-C6alkyl).
Preferred embodiments of the compounds of the invention include a single R1 sulfonamide moiety at the 7-position. The R group of the sulfonamide moiety is preferably C1-C6alkyl, substituted C1-C6alkyl, phenyl, substituted phenyl, benzyl, or substituted benzyl. Particularly preferred R groups include methyl, ethyl, propyl, butyl, phenyl, and benzyl, wherein the phenyl or benzyl group can be substituted with one or more C1-C6alkyl, C1-C6 alkoxy, hydroxy, halo, nitro, CF3, xe2x80x94Oxe2x80x94CF3, amino, or amino substituted with one or two C1-C6alkyl.
Each X is preferably C1-C6alkyl, C1-C6alkoxy, hydroxy or halo. In one embodiment, n is 1 and X is a hydroxy located at the 6-position.
The benzyl group of R2 is preferably substituted with one or more C1-C6alkoxy (e.g., methoxy, ethoxy) or halo groups (e.g., bromo, iodo). In one embodiment, the R2 group has the structure: 
wherein R4, R5, and R6 are independently selected alkoxy or halo. In one preferred embodiment, R4 and R6 are halo, such as bromo, and R5 is C1-C6alkoxy (e.g., methoxy).
As noted above, preferred embodiments include an X group at the 6-position and an R1 group at the 7-position as shown below. 
A particularly preferred embodiment of the invention provides compounds of the structure: 
wherein:
X is hydroxy;
R1 is xe2x80x94NHS(O)2R, wherein R is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, phenyl, phenyl substituted with one or more C1-C6alkyl, C1-C6alkoxy, halo, CF3, or xe2x80x94Oxe2x80x94CF3, benzyl, and benzyl substituted with one or more C1-C6alkyl, C1-C6alkoxy, halo, CF3, or xe2x80x94Oxe2x80x94CF3;
R3 is H or methyl, preferably H; and
R4, R5, and R6 are independently selected alkoxy (e.g., methoxy, ethoxy) or halo (e.g., bromo).
While racemic mixtures of compounds of the invention can be active, selective, and bioavailable, isolated isomers are ordinarily of more particular interest. The S(xe2x88x92) isomers are preferred, as they generally provided the highest selectivity and the highest bioavailability. The R(+) isomers are found to be moderately active and retain selectivity, and the R-isomers are in some cases easier to isolate.
The compounds of Formula I may be utilized per se or in the form of a pharmaceutically acceptable salt. If used, a salt of the drug compound should be both pharmacologically and pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare the free active compound or pharmaceutically acceptable salts thereof and are not excluded from the scope of this invention. Such pharmacologically and pharmaceutically acceptable salts can be prepared by reaction of the drug with an organic or inorganic acid, using standard methods detailed in the literature. Examples of useful salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicyclic, p-toluenesulfonic, tartaric, citric, methanesulphonic, formic, malonic, succinic, naphthalene-2-sulphonic and benzenesulphonic, and the like. Also, pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium, or calcium salts of a carboxylic acid group. Salts prepared from maleic acid and hydrochloric acid are particularly preferred.
Exemplary compounds of Formula I above are shown below: 
A convenient protection scheme has been devised for the synthesis of the desired xcex23-adrenoreceptor agonists of the present invention adapted from the procedures disclosed in a previous application assigned to the present assignee and designated U.S. patent application Ser. No. 09/164,047, filed Sep. 30, 1998, which is hereby incorporated by reference herein. As those of ordinary skill in the art of chemical synthesis will understand, the procedures there are adapted to the requirements of the present invention by well-known and readily understood adaptations to accommodate selection and use of differing starting reagents. The synthesis methods are generally adapted from methods disclosed in Clark, M. T.; Adejare, A.; Shams, G.; Feller, D. R.; Miller, D. D. xe2x80x9c5-fluoro- and 8fluorotrimetoquinol: selective beta 2-adrenoceptor agonistsxe2x80x9d J Med Chem 1987, 30, 86-90; Harrold, M. W.; Gerhardt, M. A.; Romstedt, K.; Feller, D. R.; Miller, D. D. xe2x80x9cSynthesis and platelet antiaggregatory activity of trimetoquinol analogs as endoperoxide/thromboxane A2 antagonistsxe2x80x9d Drug Des Deliv 1987,1, 193-207; Adejare,A.; Miller, D. D.; Fedynaj S.;Ahn, C. H.; Feller, D. R. xe2x80x9cSyntheses and betaadrenergic agonist and antiaggregatory properties of N-substituted trimetoquinol analoguesxe2x80x9d J Med Chem 1986,29,1603-9.
As illustrated in the appended examples, compounds of the invention can be formed using N-[2-(4-amino-3-benzyloxy-phenyl)-ethyl]-2-(3,5-dibromo-4-methoxyphenyl)-acetamide as a starting point, which can be synthesized as disclosed in Example 1. Isolation of the stereoisomers is performed by known techniques, including recrystallization using diasteromeric salts, chiral column separation using HPLC, adsorption chromatography, and the like.
In another aspect, the invention provides pharmaceutical formulations or compositions, both for veterinary and for human medical use, comprising a compound of Formula I as described above and one or more pharmaceutically acceptable carriers, and optionally any other therapeutic ingredients, stabilizers, or the like. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. The compositions of the invention may also include polymeric excipients/additives or carriers, e.g., polyvinylpyrrolidones, derivatized celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch (HES), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-xcex2-cyclodextrin and sulfobutylether-xcex2-cyclodextrin), polyethylene glycols, and pectin. The compositions may further include diluents, buffers, binders, disintegrants, thickeners, lubricants, preservatives (including antioxidants), flavoring agents, taste-masking agents, inorganic salts (e.g., sodium chloride), antimicrobial agents (e.g., benzalkonium chloride), sweeteners, antistatic agents, surfactants (e.g., polysorbates such as xe2x80x9cTWEEN 20xe2x80x9d and xe2x80x9cTWEEN 80xe2x80x9d, and pluronics such as F68 and F88, available from BASF), sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines, fatty acids and fatty esters, steroids (e.g., cholesterol)), and chelating agents (e.g., EDTA, zinc and other such suitable cations). Other pharmaceutical excipients and/or additives suitable for use in the compositions according to the invention are listed in xe2x80x9cRemington: The Science and Practice of Pharmacyxe2x80x9d, 19th ed., Williams and Williams, (1995), and in the xe2x80x9cPhysician""s Desk Referencexe2x80x9d, 52nd ed., Medical Economics, Montvale, N.J. (1998), and in xe2x80x9cHandbook of Pharmaceutical Excipientsxe2x80x9d, Third Ed., Ed. A. H. Kibbe, Pharmaceutical Press, 2000.
The compounds of Formula I above may be formulated in compositions including those suitable for oral, buccal, rectal, topical, nasal, ophthalmic, or parenteral (including intraperitoneal, intravenous, subcutaneous, or intramuscular injection) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing a compound of Formula I into association with a carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by bringing a compound of the invention into association with a liquid carrier to form a solution or a suspension, or alternatively, bringing a compound of the invention into association with formulation components suitable for forming a solid, optionally a particulate product, and then, if warranted, shaping the product into a desired delivery form. Solid formulations of the invention, when particulate, will typically comprise particles with sizes ranging from about 1 nanometer to about 500 microns. In general, for solid formulations intended for intravenous administration, particles will typically range from about 1 nm to about 10 microns in diameter.
The amount of the compound of Formula I in the formulation will vary depending the specific compound selected, dosage form, target patient population, and other considerations, and will be readily determined by one skilled in the art. The amount of the compound of Formula I in the formulation will be that amount necessary to deliver a therapeutically effective amount of the compound to a patient in need thereof to achieve at least one of the therapeutic effects associated with the compounds of the invention. In practice, this will vary widely depending upon the particular compound, its activity, the severity of the condition to be treated, the patient population, the stability of the formulation, and the like. Compositions will generally contain anywhere from about 1% by weight to about 99% by weight of a compound of the invention, typically from about 5% to about 70% by weight, and more typically from about 10% to about 50% by weight, and will also depend upon the relative amounts of excipients/additives contained in the composition.
In a further aspect, the present invention relates to the field of treating obesity and overweight conditions in animals, particularly humans and other mammals, and associated effects of conditions associated with obesity and overweight, including Type II diabetes mellitus (non-insulin dependent diabetes), insulin resistance, glucose intolerance, hypothyroidism, morbid obesity, and the like.
The regulatory and modulatory effect of the compounds of the present invention are believed to be dependent on continued administration over time, and the attainment of an equilibrium state which is believed to be dose dependent. In that fashion, the present invention affords the control of body fat in animals, particularly humans and other mammals, over sustained periods, at desirable levels of body fat and/or body mass indices, as defined in the medical literature.
The compounds can be formulated into pharmaceutical compositions to serve as highly selective, effective and safe xcex23-adrenoreceptor agonists to provide long-term weight control. In humans, the compositions can be administered to control body fat levels, and to maintain acceptable body fat levels over time. In domesticated animals, the compositions can be administered to attain desirably low fat content in carcass meats intended for human consumption.
The method of treatment generally includes administering a therapeutically effective amount of a compound of Formula I, optionally in a pharmaceutical composition including one or more pharmaceutically acceptable carriers. The therapeutically effective amount is preferably sufficient to stimulate, regulate and modulate metabolism of fats in adipose tissues. The therapeutically effective dosage amount of any specific formulation will vary somewhat from drug to drug, patient to patient, and will depend upon factors such as the condition of the patient and the route of delivery. As a general proposition, a dosage from about 0.5 to about 20 mg/kg body weight, preferably from about 1.0 to about 5.0 mg/kg, will have some therapeutic efficacy. When administered conjointly with other pharmaceutically active agents, even less of the compounds of the invention may be therapeutically effective.
The compounds of the invention can be administered once or several times a day. The duration of the treatment may be once per day for a period of from two to three weeks and may continue for a period of months or even years. The daily dose can be administered either by a single dose in the form of an individual dosage unit or several smaller dosage units or by multiple administration of subdivided dosages at certain intervals. Possible routes of delivery include buccally, subcutaneously, transdermally, intramuscularly, intravenously, orally, or by inhalation.